P2x7 modulators

ABSTRACT

The present invention is directed to a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application No. 61/785,558filed on Mar. 14, 2013 which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention is related compounds having P2X7 modulatingproperties, pharmaceutical compositions comprising these compounds,chemical processes for preparing these compounds and their use in thetreatment of diseases associated with P2X7 receptor activity in animals,in particular humans.

BACKGROUND OF THE INVENTION

The P2X7 receptor is a ligand-gated ion channel and is present on avariety of cell types, largely those known to be involved in theinflammatory and/or immune process, specifically, macrophages andmonocytes in the periphery and predominantly in glial cells (microgliaand astrocytes) of the CNS. (Duan and Neary, Glia 2006, 54, 738-746;Skaper et al., FASEB J 2009, 24, 337-345; Surprenant and North, Annu.Rev. Physiol. 2009, 71, 333-359). Activation of the P2X7 receptor byextracellular nucleotides, in particular adenosine triphosphate, leadsto the release of proinflammatory cytokines IL-1β and IL-18 (Muller, et.al. Am. J. Respir. Cell Mol. Biol. 2011, 44, 456-464), giant cellformation (macrophages/microglial cells), degranulation (mast cells) andL-selectin shedding (lymphocytes) (Ferrari et al., J. Immunol. 2006,176, 3877-3883; Surprenant and North, Annu. Rev. Physiol. 2009, 71,333-359). P2X7 receptors are also located on antigen-presenting cells(keratinocytes, salivary acinar cells (parotid cells)), hepatocytes,erythrocytes, erythroleukaemic cells, monocytes, fibroblasts, bonemarrow cells, neurones, and renal mesangial cells.

The importance of P2X7 in the nervous system arises primarily fromexperiments using P2X7 knock-out mice. These mice demonstrate the roleof P2X7 in the development and maintenance of pain as these mice wereprotected from the development of both adjuvant-induced inflammatorypain and partial nerve ligation induced neuropathic pain (Chessell etal., Pain 2005, 114, 386-396). In addition P2X7 knock-out mice alsoexhibit an anti-depressant phenotype based on reduced immobility inforced swim and tail suspension tests (Basso et al., Behay. Brain Res.2009, 198, 83-90). Moreover, the P2X7 pathway is linked to the releaseof the pro-inflammatory cytokine, IL-1β, which has been linked toprecipitation of mood disorders in humans (Dantzer, Immunol. AllergyClin. North Am. 2009, 29, 247-264; Capuron and Miller, Pharmacol. Ther.2011, 130, 226-238). In addition, in murine models of Alzheimer'sdisease, P2X7 was upregulated around amyloid plaques indicating a roleof this target in such pathology as well (Parvathenani et al., J. Biol.Chem. 2003, 278, 13309-13317).

In view of the clinical importance of P2×7, the identification ofcompounds that modulate P2X7 receptor function represents an attractiveavenue into the development of new therapeutic agents. Such compoundsare provided herein.

SUMMARY OF THE INVENTION

The invention is directed to the general and preferred embodimentsdefined, respectively, by the independent and dependent claims appendedhereto, which are incorporated by reference herein. One aspect of thisinvention concerns compounds of Formula (I):

wherein:n is an integer from 0-1;X is CH₂ when n is 0, or X is CH₂ or oxygen when n is 1;R₁ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionallysubstituted with halogen or alkyl; andR₂ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,thiazolyl or thiophenyl, wherein the phenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl or thiophenyl is optionallysubstituted with halogen, alkyl, hydroxy or alkoxy.

Further embodiments are provided by a pharmaceutically acceptable saltof a compound of Formula (I). It should be understood that enantiomersand diastereomers of the compounds of Formula (I) are also described, aswell as the pharmaceutically acceptable salts.

In certain embodiments, the compound of Formula (I) is a compoundselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to pharmaceuticalcompositions comprising an effective amount of at least one compound ofFormula (I), or a pharmaceutically acceptable salt of a compound ofFormula (I). Pharmaceutical compositions according to the invention mayfurther comprise one or more pharmaceutically acceptable excipients.

In another aspect, the chemical embodiments of the present invention areuseful as P2X7 receptor modulators. Thus, the invention is directed to amethod for modulating P2X7 receptor activity, including when suchreceptor is in a subject, comprising exposing P2X7 receptor to aneffective amount of at least one compound of Formula (I), or apharmaceutically acceptable salt of a compound of Formula (I).

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, comprising administeringto the subject in need of such treatment an effective amount of at leastone compound of Formula (I), or a pharmaceutically acceptable salt of acompound of Formula (I). Additional embodiments of methods of treatmentare set forth in the detailed description.

In another aspect, method of studying isotopically labeled compounds inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. For example, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments of this invention include methods of making acompound of Formula (I), or a pharmaceutically acceptable salt of acompound of Formula (I).

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF THE INVENTION

A compound of Formula (I):

wherein:n is an integer from 0-1;X is CH₂ when n is 0, or X is CH₂ or oxygen when n is 1;R₁ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionallysubstituted with halogen or alkyl; andR₂ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,thiazolyl or thiophenyl, wherein the phenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl or thiophenyl is optionallysubstituted with halogen, alkyl, hydroxy or alkoxy.

Enantiomers and diastereomers of the compounds of Formula (I) are alsowithin the scope of the invention. Also within the scope of theinvention are the pharmaceutically acceptable salts of the compounds ofFormula (I), as well as the pharmaceutically acceptable salts of theenantiomers and diastereomers of the compounds of Formula (I).

The following are various embodiments of compounds of Formula (I), thepharmaceutically acceptable salts of the compounds of Formula (I), aswell as the pharmaceutically acceptable salts of the enantiomers anddiastereomers of the compounds of Formula (I):

In preferred embodiments, n is 0 and X is CH₂.

In certain embodiments, n is 1 and X is CH₂. In other embodiments, n is1 and X is oxygen.

In certain embodiments, R₁ is phenyl.

In other embodiments, R₁ is phenyl substituted with halogen or alkyl.

In other embodiments, R₁ is phenyl di-substituted with halogen, forexample chlorine.

In other embodiments, R₁ is phenyl di-substituted with alkyl, forexample methyl and trifluoromethyl.

In other embodiments, R₁ is phenyl di-substituted with halogen andalkyl, for examples chlorine and trifluoromethyl.

In other embodiments, R₁ is phenyl ortho substituted with halogen, forexample chlorine.

In other embodiments, R₁ is phenyl meta substituted with alkyl, forexample trifluoromethyl.

In other embodiments, R₁ is phenyl di-substituted with halogen at theortho and para positions, for example chlorine.

In other embodiments, R₁ is phenyl di-substituted with alkyl at theortho and meta positions, for example methyl at the ortho position andtrifluoromethyl at the meta position.

In other embodiments, R₁ is phenyl tri-substituted with halogen, forexample two chlorines and one fluorine.

In other embodiments, R₁ is phenyl tri-substituted with halogen at theortho, meta and para positions, for example two chlorines at the orthoand para positions and one fluorine at the meta position, or twochlorines at the ortho and meta positions and one fluorine at the paraposition. In preferred embodiments, the ortho and para substitutions areadjacent to the meta substitution.

In other embodiments, R₁ is phenyl tri-substituted with halogen andalkyl.

In other embodiments, R₁ is phenyl tri-substituted with halogen andalkyl at the ortho, meta and para positions. In preferred embodiments,the ortho and para substitutions are adjacent to the meta substitution.

In certain embodiments, R₁ is pyridinyl.

In other embodiments, R₁ is pyridinyl that is attached through the4-position carbon atom.

In other embodiments, R₁ is pyridinyl substituted with halogen or alkyl,for example chlorine or fluorine and trifluoromethyl or methyl.

In other embodiments, R₁ is pyridinyl that is substituted with halogenand alkyl, for example, chlorine and trifluoromethyl or fluorine andtrifluoromethyl.

In other embodiments, R₁ is pyridinyl that is di-substituted with alkylat a meta and an ortho position, for example trifluoromethyl at a metaposition and methyl at an ortho position. In preferred embodiments, thealkyl substitutions are adjacent to each other on the phenyl ring.

In other embodiments, R₁ is pyridinyl that is di-substituted with alkylat a meta position and halogen at an ortho position, for examplestrifluoromethyl at a meta position and chlorine or fluorine at an orthoposition. In preferred embodiments, the alkyl and halogen substitutionsare adjacent to each other.

In certain embodiments, R₂ is phenyl.

In certain embodiments, R₂ is phenyl substituted with halogen, forexamples, chlorine or fluorine.

In other embodiments, R₂ is phenyl substituted with halogen at the paraposition, for example fluorine at the para position.

In other embodiments, R₂ is pyridinyl.

In other embodiments, R₂ is pyridinyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is pyridinyl that is attached through the3-position carbon atom.

In other embodiments, R₂ is pyridinyl that is substituted with alkyl,for example methyl or trifluoromethyl.

In other embodiments, R₂ is pyridinyl that is substituted with halogen,for example chlorine or fluorine.

In other embodiments, R₂ is pyridinyl that is attached through the2-position carbon atom and substituted with halogen, for examplechlorine or fluorine.

In other embodiments, R₂ is pyridinyl that is substituted with halogenat the 5-position of the carbon atom, for example chlorine or fluorineat the 5-position.

In other embodiments, R₂ is pyridinyl that is substituted with alkoxy,for example methoxy, ethoxy, propoxy, difluoromethoxy ortrifluoromethoxy.

In other embodiments, R₂ is pyridinyl that is di-substituted with alkyland halogen.

In other embodiments, R₂ is pyridinyl that is substituted at the3-position carbon atom.

In other embodiments, R₂ is pyridinyl that is substituted with halogenat the 3-position carbon atom, for example fluorine.

In other embodiments, R₂ is pyridinyl that is substituted at the4-position carbon atom.

In other embodiments, R₂ is pyridinyl that is substituted with alkyl atthe 4-position carbon atom, for example with methyl or trifluoromethyl.

In other embodiments, R₂ is pyridinyl that is substituted with alkoxy atthe 4-position carbon atom, for example with methoxy.

In other embodiments, R₂ is pyridinyl that is substituted at the5-position carbon atom.

In other embodiments, R₂ is pyridinyl that is substituted at the5-position carbon atom with halogen.

In other embodiments, R₂ is pyridinyl that is substituted at the6-position carbon atom.

In other embodiments, R₂ is pyridinyl that is substituted with alkyl atthe 6-position carbon atom, for example methyl.

In other embodiments, R₂ is pyridinyl that is di-substituted at the 4-and 5-position carbon atom with halogen and alkoxy, for example fluorineand methoxy.

In other embodiments, R₂ is pyridinyl that is di-substituted at the 5-and 6-position carbon atom with alkyl and halogen, for example methyland fluorine.

In other embodiments, R₂ is pyrazinyl.

In other embodiments, R₂ is pyrazinyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is pyrrolyl.

In other embodiments, R₂ is pyrrolyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is pyrimidinyl.

In other embodiments, R₂ is pyrimidinyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is pyrimidinyl substituted with halogen.

In other embodiments, R₂ is pyrimidinyl substituted with halogen at the5-position carbon atom.

In other embodiments, R₂ is pyrimidinyl substituted with fluorine at the5-position carbon atom.

In other embodiments, R₂ is pyrazolyl.

In other embodiments, R₂ is pyrazolyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is pyrazolyl that is attached through the3-position carbon atom.

In other embodiments, R₂ is pyrazolyl that is attached through the5-position carbon atom.

In other embodiments, R₂ is pyrazolyl that is substituted with alkyl.

In other embodiments, R₂ is pyrazolyl that is substituted with alkyl atthe 3-position carbon atom.

In other embodiments, R₂ is pyrazolyl that is substituted with methyl atthe 3-position carbon atom.

In other embodiments, R₂ is thiazolyl.

In other embodiments, R₂ is thiazolyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is thiazolyl that is attached through the4-position carbon atom.

In other embodiments, R₂ is thiazolyl that is attached through the5-position carbon atom.

In other embodiments, R₂ is thiazolyl that is substituted with alkyl.

In other embodiments, R₂ is thiazolyl that is substituted with alkyl atthe 2-position carbon atom.

In other embodiments, R₂ is thiazolyl that is substituted with alkyl atthe 4-position carbon atom.

In other embodiments, R₂ is thiophenyl.

In other embodiments, R₂ is thiophenyl that is attached through the2-position carbon atom.

In other embodiments, R₂ is thiophenyl that is attached through the3-position carbon atom.

In other embodiments, R₂ is thiophenyl that is substituted with alkyl atthe 5-position carbon atom.

In other embodiments, R₂ is thiazolyl that is substituted with halo atthe 5-position carbon atom.

In certain embodiments, R₁ is phenyl and R₂ is phenyl.

In certain embodiments, R₁ is phenyl substituted with halogen and R₂ isphenyl substituted with halogen.

In certain embodiments, n is 0, R₁ is phenyl substituted with halogenand alkyl and R₂ is phenyl substituted with halogen.

In certain embodiments, R₁ is phenyl and R₂ is pyridinyl.

In other embodiments, R₁ is phenyl substituted with alkyl and halogenand R₂ is pyridinyl.

In other embodiments, R₁ is phenyl substituted with alkyl and halogenand

R₂ is pyridinyl substituted with halogen.

In other embodiments n is O, R₁ is phenyl and R₂ is pyridinyl.

In other embodiments n is O, R₁ is phenyl di-substituted at adjacentortho and meta positions, and R₂ is pyridinyl.

In other embodiments n is O, R₁ is phenyl di-substituted at adjacentortho and meta positions, and R₂ is pyridinyl substituted with halogen.

In certain embodiments, R₁ is phenyl and R₂ is thiazolyl.

In certain embodiments, R₁ is phenyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted thiazolyl.

In certain embodiments, R₁ is pyridinyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted thiazolyl.

In certain embodiments, R₁ is phenyl and R₂ is pyrimidinyl.

In certain embodiments, R₁ is phenyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted pyrimidinyl.

In certain embodiments, R₁ is pyridinyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted pyrimidinyl.

In certain embodiments, R₁ is phenyl and R₂ is pyrazinyl.

In certain embodiments, R₁ is phenyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted pyrazinyl.

In certain embodiments, R₁ is pyridinyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted pyrazinyl.

In certain embodiments, R₁ is phenyl and R₂ is thiophenyl.

In certain embodiments, R₁ is phenyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted thiophenyl.

In certain embodiments, R₁ is pyridinyl substituted with one to threehalogen and alkyl and R₂ is optionally substituted thiophenyl.

An additional embodiment of the invention is a compound selected fromthe group consisting of those presented in Table 1:

TABLE 111-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)pheny]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(3-methyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methyl-1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methyl-1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[3-chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1H-pyrrol-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(3-chloro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone((2-methyl-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(3-methyl-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2,4-dichloro-3-fluorophenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(3-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(3,5-difluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone((2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(difluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-hydroxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-ethoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-isopropoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichloro-4-fluorophenyl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichlorophenyl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]thazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)-((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

An additional embodiment of the invention is a pharmaceuticalcomposition, comprising:

(a) an effective amount of at least one compound of Formula (I):

wherein:n is an integer from 0-1;X is CH₂ when n is 0, or X is CH₂ or oxygen when n is 1;R₁ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionallysubstituted with halogen or alkyl; andR₂ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,thiazolyl or thiophenyl, wherein the phenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl or thiophenyl is optionallysubstituted with halogen, alkyl, hydroxy or alkoxy; andthe pharmaceutically acceptable salts of the compounds of Formula (I),as well as the pharmaceutically acceptable salts of the enantiomers anddiastereomers of the compounds of Formula (I); and

(b) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, comprising administeringto a subject in need of such treatment an effective amount of at leastone compound of Formula (I):

wherein:n is an integer from 0-1;X is CH₂ when n is 0, or X is CH₂ or oxygen when n is 1;R₁ is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionallysubstituted with halogen or alkyl; andR₂ is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,thiazolyl or thiophenyl, wherein the phenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl or thiophenyl is optionallysubstituted with halogen, alkyl, hydroxy or alkoxy; andthe pharmaceutically acceptable salts of the compounds of Formula (I),as well as the pharmaceutically acceptable salts of the enantiomers anddiastereomers of the compounds of Formula (I).

In preferred embodiments of the inventive method, the disease, disorder,or medical condition is selected from: diseases of the autoimmune andinflammatory system such as: rheumatoid arthritis, osteoarthritis,psoriasis, septic shock, allergic dermatitis, asthma, allergic asthma,mild to severe asthma, steroid resistant asthma, idiopathic pulmonaryfibrosis, allergic rhinitis, chronic obstructive pulmonary disease andairway hyper-responsiveness; diseases of the nervous and neuro-immunesystem such as acute and chronic pain states of neuropathic pain,inflammatory pain, spontaneous pain (diabetic neuropathy, postherpeticneuralgia, low back pain, chemotherapy-induced neuropathic pain,fibromyalgia) (Romagnoli, R, et. al., Expert Opin. Ther. Targets, 2008,12(5), 647-661), and diseases involved with and withoutneuroinflammation of the central nervous system such as mood disorders(major depression, major depressive disorder, treatment resistantdepression, bipolar disorder, anxious depression, anxiety) (Friedle, SA, et. al., Recent Patents on CNS Drug Discovery, 2010, 5, 35-45,Romagnoli, R, et. al., Expert Opin. Ther. Targets, 2008, 12(5),647-661), cognition, sleep disorders, multiple sclerosis (Sharp A J, et.al., J Neuroinflammation. 2008 Aug. 8; 5:33, Oyanguren-Desez O, et. al.,Cell Calcium. 2011 November; 50(5):468-72, Grygorowicz T, et. al.,Neurochem Int. 2010 December; 57(7):823-9), epileptic seizures (Engel T,et. al., FASEB J. 2012 April; 26(4):1616-28, Kim J E, et. al. NeurolRes. 2009 November; 31(9):982-8, Avignone E, et. al., J. Neurosci. 2008Sep. 10; 28(37):9133-44), Parkinson's disease (Marcellino D, et. al., JNeural Transm. 2010 June; 117(6):681-7), schizophrenia, Alzheimer'sdisease (Diaz-Hernandez J I, et. al., Neurobiol Aging. 2012 August;33(8):1816-28, Delarasse C, J Biol. Chem. 2011 Jan. 28; 286(4):2596-606,Sanz J M, et. al., J. Immunol. 2009 Apr. 1; 182(7):4378-85),Huntington's disease (Diaz-Hernández M, et. Al., FASEB J. 2009 June;23(6):1893-906), autism, spinal cord injury and cerebralischemia/traumatic brain injury (Chu K, et. al., J Neuroinflammation.2012 Apr. 18; 9:69, Arbeloa J, et. al, Neurobiol Dis. 2012 March;45(3):954-61).

P2X7 antagonism may also be beneficial in several stress-relateddisorders. In addition, P2X7 intervention may be beneficial in diseasesof the cardiovascular, metabolic, gastrointestinal and urogenitalsystems such as diabetes (Arterioscler Thromb Vasc Biol. 2004 July;24(7):1240-5), thrombosis (Furlan-Freguia C, et. al., J Clin Invest.2011 July; 121(7):2932-44), irritable bowel syndrome, Crohn's disease,ischemic heart disease, hypertension (Ji X, et. al., Am J Physiol RenalPhysiol. 2012 October; 303(8):F1207-15), myocardial infarction, andlower urinary tract dysfunction such as incontinence. P2X7 antagonismmay also present a novel therapeutic strategy for skeletal disorders,namely osteoporosis/osteopetrosis and may also modulate secretoryfunction of exocrine glands. It is also hypothesized that blocking P2X7may also be beneficial in glaucoma, interstitial cystitis (Martins J P,et. al., Br J. Pharmacol. 2012 January; 165(1):183-96) and lower urinarytract syndrome (Br J. Pharmacol. 2012 January; 165(1):183-96), IBD/IBS(J. Immunol. 2011 Aug. 1; 187(3):1467-74. Epub 2011 Jun. 22),Sleep,RA/OA, Cough/COPD/asthma, cardiovascular disease, GN, uretericobstruction, diabetes mellitus, hypertension, sepsis, ischaemia,Amyotrophic Lateral Sclerosis, Chaga's Disease, Chlamydia,Neuroblastoma, Tuberculosis, Polycystic Kidney Disease, and migraine.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity, wherein the disease,disorder, or medical condition is selected from the group consisting of:rheumatoid arthritis, osteoarthritis, psoriasis, septic shock, allergicdermatitis, asthma, allergic asthma, mild to severe asthma, steroidresistant asthma, idiopathic pulmonary fibrosis, allergic rhinitis,chronic obstructive pulmonary disease and airway hyper-responsiveness;diseases of the nervous and neuro-immune system such as acute andchronic pain states of neuropathic pain, inflammatory pain, spontaneouspain (diabetic neuropathy, postherpetic neuralgia, low back pain,chemotherapy-induced neuropathic pain, fibromyalgia); diseases involvedwith and without neuroinflammation of the central nervous system such asmood disorders (major depression, major depressive disorder, treatmentresistant depression, bipolar disorder, anxious depression, anxiety),cognition, sleep disorders, multiple sclerosis, epileptic seizures,Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington'sdisease, autism, spinal cord injury and cerebral ischemia/traumaticbrain injury, stress-related disorders; diseases of the cardiovascular,metabolic, gastrointestinal and urogenital systems such as diabetes,diabetes mellitus, thrombosis, irritable bowel syndrome, irritable boweldisease, Crohn's disease, ischemic heart disease, ischaemia,hypertension, cardiovascular disease, myocardial infarction, and lowerurinary tract dysfunction such as incontinence, lower urinary tractsyndrome, Polycystic Kidney Disease, Glomerulonephritis; skeletaldisorders, namely osteoporosis/osteopetrosis: and glaucoma, interstitialcystitis, cough, ureteric obstruction, sepsis, Amyotrophic LateralSclerosis, Chaga's Disease, chlamydia, neuroblastoma, Tuberculosis, andmigraine.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by P2X7 receptor activity wherein the disease,disorder or medical condition is treatment resistant depression.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 6 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. Alkyl groups of the invention can besubstituted with, for example, halogen atoms. One exemplary substitutentis fluoro. Preferred substituted alkyl groups of the invention includedi- or trihalogenated alkyl groups such as difluoromethyl ortrifluoromethyl groups.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. The alkyl group of the alkoxy of the invention can besubstituted with, for example, halogen atoms (so that the alkoxy of theinvention is a halogenated alkoxy such as difluoromethoxy). Oneexemplary substitutent of the alkyl group of the alkoxy of the inventionis fluoro. Preferred substituted alkyl groups of alkoxy of the inventioninclude di- or trihalogenated alkyl groups such as difluoromethyl ortrifluoromethyl groups.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “phenyl” represents the following moiety:

Phenyl groups of the inventions can be optionally substituted with, forexample, one or more halogens and/or one or more alkyl groups. Exemplarysubstitutents are fluorine, bromine, chlorine, methyl, trifluoromethyl.Preferred substituted phenyl groups of the invention are substitutedwith one, two, or three halogen, for example two chlorines, twofluorines, or one fluorine and two chlorines. Other preferredsubstituted phenyl groups of the invention are substituted with one ortwo alkyl groups, for example a methyl and trifluoromethyl group. Otherpreferred substituted phenyl groups of the invention are substitutedwith one or two halogens and one or two alkyl groups, for example onechlorine and one trifluoromethyl group, one fluorine and onetrifluoromethyl group, one fluorine and one methyl group, or twohalogens (such as a fluorine and chlorine) and one trifluoromethylgroup.

The term “pyridinyl” represents the following moiety:

The pyridinyl moiety can be attached through any one of the 2-, 3-, 4-,5-, or 6-position carbon atoms. Pyridinyl groups of the invention can beoptionally substituted with, for example, one or more alkyl, alkoxy,hydroxy and/or halogen groups. Preferred substituted pyridinyl groups ofthe invention are substituted with one, two, or three halogens, forexample one fluorine, one chlorine, two chlorines, two fluorines, or onefluorine and two chlorines. Other preferred substituted pyridinyl groupsof the invention are substituted with one or two alkyl groups, forexample a methyl group, a trifluoromethyl group, or a methyl andtrifluoromethyl group. Other preferred substituted pyridinyl groups ofthe invention are substituted with one or two halogens and one or twoalkyl groups, for example one chlorine and one trifluoromethyl group,one fluorine and one trifluoromethyl group, one fluorine and one methylgroup, or two halogens (such as a fluorine and chlorine) and onetrifluoromethyl group. Another preferred substituted pyridinyl group isone or two hydroxyl groups. Another preferred substituted pyridinylgroup is one methoxy, difluoromethoxy, trifluoromethoxy, ethoxy orpropoxy groups. Another preferred substituted pyridinyl group is onealkoxy and one halogen, for example one methoxy and one fluorine.

The term “pyrimidinyl” represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-,5-, or 6-position carbon atoms. Within the scope of the invention,“pyrimidinyl” groups of the invention can be substituted with one ormore halogens, for example one fluorine.

The term “pyrazinyl” represents the following moiety:

The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-,or 6-position carbon atoms.

The term “pyrazolyl” represents the following moiety:

The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-,4-, or 5-position carbon atoms. Pyrazolyl groups of the invention can beoptionally substituted with, for example, one or more alkyl groups, forexample, one methyl group.

The term “pyrrolyl” represents the following moiety:

The pyrrolyl moiety can be attached through any one of the 2-, 3-, 4-,or 5-position carbon atoms.

The term “thiazolyl” represents the following moiety:

The thiazolyl moiety can be attached through any one of the 2-, 4-, or5-position carbon atoms. Thiazolyl groups of the invention can beoptionally substituted with, for example, one or more alkyl groups, forexample, one methyl group.

The term “thiophenyl” represents the following moiety:

The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-,or 5-position carbon atoms. Thiophenyl groups of the invention can beoptionally substituted with, for example, one or more alkyl or halogengroups, for example, one methyl group or one chlorine.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, ^(5th) ed. a (2005), describing, inter alia, buffer solutionsand how the concentrations of the buffer constituents relate to the pHof the buffer. For example, a buffered solution is obtained by addingMgSO₄ and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH ofthe solution at about 7.5.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers of the compounds of the generalformula, and mixtures thereof, are considered within the scope of theformula. Thus, any formula given herein is intended to represent aracemate, one or more enantiomeric forms, one or more diastereomericforms, one or more atropisomeric forms, and mixtures thereof.Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, and a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of T1 electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is,conformational isomers that occur when the rotation leading to differentconformations is hindered, resulting a rotational energy barrier to beovercome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

Certain examples contain chemical structures that are depicted as anabsolute enantiomer but are intended to indicate enatiopure materialthat is of unknown configuration. In these cases (R*) or (S*) is used inthe name to indicate that the absolute stereochemistry of thecorresponding stereocenter is unknown. Thus, a compound designated as(R*) refers to an enantiopure compound with an absolute configuration ofeither (R) or (S). In cases where the absolute stereochemistry has beenconfirmed, the structures are named using (R) and (S).

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) or pharmaceutically acceptable salts of compounds ofFormula (I) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of compounds of the invention withone or more solvents, either in solution or as a solid or crystallineform. In some embodiments, the solvent is water and then the solvatesare hydrates. In addition, certain crystalline forms of compounds ofFormula (I) or pharmaceutically acceptable salts of compounds of Formula(I) may be obtained as co-crystals. In certain embodiments of theinvention, compounds of Formula (I) were obtained in a crystalline form.In other embodiments, crystalline forms of compounds of Formula (I) werecubic in nature. In other embodiments, pharmaceutically acceptable saltsof compounds of Formula (I) were obtained in a crystalline form. Instill other embodiments, compounds of Formula (I) were obtained in oneof several polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) convert in solution between one or morecrystalline forms and/or polymorphic forms.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent; and R—COO⁻ _((sol)) refers to the dissociated form of thecompound in a solvent, such as the dissociated form of the compound inan aqueous environment, whether such dissociated form derives fromR—COOH, from a salt thereof, or from any other entity that yields R—COO⁻upon dissociation in the medium being considered. In another example, anexpression such as “exposing an entity to compound of formula R—COOH”refers to the exposure of such entity to the form, or forms, of thecompound R—COOH that exists, or exist, in the medium in which suchexposure takes place. In still another example, an expression such as“reacting an entity with a compound of formula R—COOH” refers to thereacting of (a) such entity in the chemically relevant form, or forms,of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine,such as ²H, 3H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I), preferably of those described above and of thespecific compounds exemplified herein, and methods of treatment usingsuch salts.

The term “pharmaceutically acceptable” means approved or approvable by aregulatory agency of Federal or a state government or the correspondingagency in countries other than the United States, or that is listed inthe U.S. Pharmcopoeia or other generally recognized pharmacopoeia foruse in animals, and more particularly, in humans.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. It should possess the desiredpharmacological activity of the parent compound. See, generally, G. S.Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient SaltSelection based on Analysis of the Orange Book Database”, J. Med. Chem.,2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, J PharmSci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties,Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich,2002. Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-D-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I), and treatment methods employing suchpharmaceutically acceptable prodrugs. The term “prodrug” means aprecursor of a designated compound that, following administration to asubject, yields the compound in vivo via a chemical or physiologicalprocess such as solvolysis or enzymatic cleavage, or under physiologicalconditions (e.g., a prodrug on being brought to physiological pH isconverted to the compound of Formula (I)). A “pharmaceuticallyacceptable prodrug” is a prodrug that is non-toxic, biologicallytolerable, and otherwise biologically suitable for administration to thesubject. Illustrative procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and aminogroups may also yield prodrugs. Carbonate derivatives, sulfonate esters,and sulfate esters of hydroxy groups may also provide prodrugs.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group may be an alkyl ester, optionallysubstituted with one or more ether, amine, or carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, is also useful to yield prodrugs. Prodrugs of this typemay be prepared as described in Robinson et al., J Med. Chem. 1996, 39(1), 10-18. Free amines can also be derivatized as amides, sulfonamidesor phosphonamides. All of these prodrug moieties may incorporate groupsincluding ether, amine, and carboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I), which may also be used inthe methods of the invention. A “pharmaceutically active metabolite”means a pharmacologically active product of metabolism in the body of acompound of Formula (I) or salt thereof. Prodrugs and active metabolitesof a compound may be determined using routine techniques known oravailable in the art. See, e.g., Bertolini, et al., J Med. Chem. 1997,40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86 (7), 765-767;Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of the present invention are useful as modulators of theP2X7 receptor in the methods of the invention. As such modulators, thecompounds may act as antagonists, agonists, or inverse agonists. Theterm “modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize or down-regulate the P2X7 receptor expression or activity,and “activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate P2X7 receptor expression or activity.

The term “treat”, “treatment” or “treating” as used herein is intendedto refer to administration of an active agent or composition of theinvention to a subject for the purpose of affecting a therapeutic orprophylactic benefit through modulation of P2X7 receptor activity.Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition mediated through modulation of P2X7 receptoractivity. The term “subject” refers to a mammalian patient in need ofsuch treatment, such as a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by P2X7 receptor activity, suchas: rheumatoid arthritis, osteoarthritis, psoriasis, septic shock,allergic dermatitis, asthma, allergic asthma, mild to severe asthma,steroid resistant asthma, idiopathic pulmonary fibrosis, allergicrhinitis, chronic obstructive pulmonary disease (COPD) and airwayhyper-responsiveness; diseases of the nervous and neuro-immune systemsuch as acute and chronic pain states of neuropathic pain, inflammatorypain, spontaneous pain (diabetic neuropathy, postherpetic neuralgia, lowback pain, chemotherapy-induced neuropathic pain, fibromyalgia);diseases involved with and without neuroinflammation of the CNS such asmood disorders (major depression, major depressive disorder, treatmentresistant depression, bipolar disorder, anxious depression, anxiety),cognition, sleep disorders, multiple sclerosis, epileptic seizures,Parkinson's disease, schizophrenia, Alzheimer's disease, Huntington'sdisease, autism, spinal cord injury and cerebral ischemia/traumaticbrain injury, stress-related disorders; diseases of the cardiovascular,metabolic, gastrointestinal and urogenital systems such as diabetes,diabetes mellitus, thrombosis, irritable bowel syndrome, IBD, Crohn'sdisease, ischemic heart disease, ischaemia, hypertension, cardiovasculardisease, myocardial infarction, and lower urinary tract dysfunction suchas incontinence, lower urinary tract syndrome, Polycystic KidneyDisease, Glomerulonephritis, (GN); skeletal disorders, namelyosteoporosis/osteopetrosis: and glaucoma, interstitial cystitis, cough,ureteric obstruction, sepsis, Amyotrophic Lateral Sclerosis, Chaga'sDisease, chlamydia, neuroblastoma, Tuberculosis, and migraine.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of compounds of Table 1or included with such an agent in a pharmaceutical composition accordingto the invention. In an exemplary embodiment, additional activeingredients are those that are known or discovered to be effective inthe treatment of conditions, disorders, or diseases mediated by P2X7activity, such as another P2X7 modulator or a compound active againstanother target associated with the particular condition, disorder, ordisease. The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of an active agent according to the invention), decreaseone or more side effects, or decrease the required dose of the activeagent according to the invention.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Synthetic procedures described in the Schemes below are meant todescribe the synthesis of intermediates and general procedures toprepare embodiments of the invention. Variables presented in the schemesare intended to refer to the synthesis described in that scheme.

Compound IA can be converted to compound IIA by reaction with Lawesson'sreagent, in a solvent such as THF, diethyl ether or DCM. This reactionmay be performed at room temperature or heated overnight at or near theboiling point of the solvent.

Compound IIA may be converted to amine IIIA by treatment with analkylating agent such as methyl iodide in a solvent such as DCM or DMF,at a temperature of between room temperature and 40° C. for between 1and 48 hours.

Compound IVA may be converted to compound VA by treatment with hydrazinemonohydrate in a solvent such as an alcohol, DCM or DMF at a temperaturenear room temperature for from 1 to 25 hours. Compound VIA may beconverted to compound VIIA by treatment with an appropriate acylatingagent such as oxalyl chloride in the presence of a catalyst such as DMFin a solvent such as DCM or DMF for from 1 to 8 hours. Compound VIIA maythen also be converted to compound VA by treatment with hydrazinemonohydrate in a solvent such as an alcohol, DCM or DMF at a temperaturenear room temperature for from 1 to 12 hours. If compounds of type IVAor VIA are not commercially available, one skilled in the art willrealize there are numerous methods for synthesizing these compounds.These may include hydrolysis of the corresponding nitrile to afford VIAfollowed by esterification to give IVA. The nitrile in turn can beobtained from a cross-coupling reaction with a suitable halogencontaining compound. Or VIA can be directly formed from the halogencompound via metal halogen exchange followed by quenching with CO₂. IVAor VIA can also be formed by oxidation of a suitable methyl substitutedcompound with a reagent, such as, KMnO₄ followed by esterification.These compounds can also be formed by oxidation of an appropriatelysubstituted hydroxymethyl compound in either one or two steps to affordVIA.

Compound IIIA may be converted to compound VIIIA by the addition ofcompound VA and a suitable base such as potassium t-butoxide in analcohol solvent such as methanol. This reaction can be performed at atemperature from room temperature to 120° C. for from 30 minutes to 48hours. Compound VIIIA can then be converted to compound I×A by additionof a suitable acid such as HCl or TFA, preferably TFA in a solvent suchas DCM, DCE or dioxane. This reaction can be performed at a temperaturefrom room temperature to 50° C. for from 30 minutes to 24 hours.

Compound I×A may then be converted to compound XA by the addition ofVIIA and a suitable base such as triethylamine or diisopropylethylaminein a solvent such as DCM, DCE or dioxane at a temperature from roomtemperature to 50° C. for from 30 minutes to 24 hours. Alternativelycompound VIIA may be converted to compound XA using compound VIA andusing amide coupling conditions such as HATU, DIPEA in a solvent such asDCM or DMF.

Compound XIA may be converted to compound XIIIA by the addition of XIIAand a suitable base such as sodium hydride in a solvent such as THF ordioxane at a temperature from room temperature to 50° C. for from 30minutes to 24 hours. Compound XIIIA may then be converted to compoundXIVA using as suitable oxidant such as oxalyl chloride and DMSO in asuitable solvent such as DCM, DCE or THF. Compound XIVA may be convertedto compound XVA by treatment with an acid such as HCl or TFA followed bythe addition of a suitable reductant such as sodiumtriacetoxyborohydride in a suitable solvent such as THF or dioxane at atemperature from room temperature to 60° C. for from 30 minutes to 24hours. Compound XVA may be converted to compound XVIA by reaction with areagent used for the protection of primary amines, such astrifluoroethyl acetate in a solvent such as DCM, DCE or THF at atemperature from room temperature to 50° C. for from 30 minutes to 24hours. Compound XVIA may then be converted to compound XVIIA by reactionwith (Boc)₂O in a suitable solvent such as DCM or THF at a temperaturearound room temperature for from 30 minutes to 24 hours. Compound XVIIAmay then be converted to compound XVIIIA by addition of a suitable basesuch as potassium carbonate in a suitable solvent such as an alcohol,preferably methanol or ethanol at a temperature from room temperature to70° C. for from 30 minutes to 48 hours. Compound XVIIIA may then beconverted to XIXA by the procedures described in Schemes 1-3.

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄.

Where mixtures, solutions, and extracts were “concentrated”, they weretypically concentrated on a rotary evaporator under reduced pressure.Reactions under microwave irradiation conditions were carried out in aBiotage Initiator or OEM Discover instrument.

Normal-phase silica gel column chromatography (sgc) was performed onsilica gel (SiO₂) using prepackaged cartridges, eluting with 2 MNH₃/MeOH in CH₂Cl₂ unless otherwise indicated.

Preparative reverse-phase high performance liquid chromatography (HPLC)was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 μm, 30×100mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH₄OH)over 12 to 18 min, and a flow rate of 30 mL/min.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a JASCO preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted between at100-150 bar with a flow rate ranging from 40-60 mL/min. The columns usedwere heated to 35-40° C.

Compounds obtained as HCl salts were prepared by the addition of 1M HClin diethyl ether to a CH₂Cl₂ solution of the free base, followed byconcentration.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 9 (Advanced ChemistryDevelopment, Toronto, Ontario, Canada).

Abbreviations and acronyms used herein include the following:

Term Acronym High-pressure liquid chromatography HPLCDiisopropylethylamine DIPEA Tetrahydrofuran THF tert-Butylcarbamoyl bocDichloromethane DCM Dichloroethane DCE Trifluoroacetic acid TFAN,N-Dimethylformamide DMF Methanol MeOH Ethanol EtOH Isopropanol IPA oriPrOH Potassium tert-butoxide KOtBu n-Butanol nBuOH Ethyl Acetate EtOAc,or EA Triethylamine TEA 2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATUtetramethylaminium hexafluorophosphate N-(3-Dimethylaminopropyl)-N′-EDCI ethylcarbodiimide 1-Hydroxybenzotriazole HOBt Supercritical FluidChromatography SFC Isopropyl amine iPrNH₂ Not tested NT

Intermediate A: tert-Butyl2-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

tert-Butyl 2-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate wasprepared according to the procedures in WO 2001042245.

Intermediate B: tert-Butyl2-thioxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate

To a solution of tert-butyl2-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate (733 mg, 3.05 mmol) inTHF (10 mL) was added Lawesson's reagent (700 mg, 1.68 mmol). Themixture was stirred at room temperature overnight and then concentratedin vacuo. The residue was dissolved in EtOAc and washed 3× withsaturated aqueous NaHCO₃ solution. The combined aqueous layers wereextracted several times with EtOAc and the combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waschromatographed on SiO₂ eluting with EtOAc/Hex to afford the titlecompound as a colorless foam (622 mg, 79%). MS (ESI): mass calcd.C₁₂H₂₀N₂O₂S, 256.12; m/z found, 257.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.54-8.20 (m, 1H), 5.23-4.97 (m, 1H), 4.66-4.33 (m, 1H), 3.81-3.63 (m,1H), 3.28-3.17 (m, 1H), 2.22-2.11 (m, 1H), 1.90-1.58 (m, 5H), 1.47 (s,9H).

Intermediate C:(E/Z)-(9-(tert-butoxycarbonyl)-3,9-diazabicyclo[3.3.1]nonan-2-ylidene)(methyl)sulfoniumiodide

To a solution of Intermediate B (346 mg, 1.35 mmol) in DCM (5 mL) wasadded MeI (0.42 mL, 6.74 mmol). The mixture was stirred at roomtemperature for 24 h and then concentrated in vacuo to afford the titlecompound as an orange foam (540 mg, 100%). MS (ESI): mass calcd.C₁₃H₂₂N₂O₂S, 270.14; m/z found, 271.1 [M+H]⁺.

Intermediate D: Pyrimidine-2-carbohydrazide

To a slurry of methylpyrimidine-2-carboxylate (1.0 g, 7.2 mmol) in EtOH(5.6 mL) was added hydrazine monohydrate (0.72 mL, 14 mmol). Thereaction mixture became homogeneous and after 5 min a precipitateformed. Stirring was continued for 1 h. The mixture was filtered, andthe collected solid was washed with additional EtOH to provide thedesired product as a beige solid (720 mg, 72%). MS (ESI): mass calcd.C₅H₆N₄O, 138.1; m/z found, 139.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆):10.06 (s, 1H), 8.92 (d, J=4.9 Hz, 2H), 7.64 (t, J=4.9 Hz, 1H), 4.64 (s,2H).

Intermediate E: 2-Chloro-3-(trifluoromethyl)benzoyl chloride

To a suspension of 2-chloro-3-(trifluoromethyl)benzoic acid (15 g, 67mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was addedoxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir(vigorous bubbling) for 4 h and concentrated to an oily solid whichbecame solid after overnight drying on high vacuum.

Intermediate F: 5-Fluoropyrimidine-2-carbohydrazide

Intermediate F, step a: methyl 5-fluoropyrimidine-2-carboxylate

To a solution of 5-fluoropyrimidine-2-carbonitrile (513 mg, 4.17 mmol)in MeOH (5 mL) was added 5 mL of concentrated HCl. The mixture wasstirred at 80° C. for 2 h. The solution was allowed to cool to roomtemperature and then treated with a small amount of saturated aqueousNaHCO₃ solution and a larger amount of solid NaHCO₃. The solution wasused to keep everything homogeneous. When the pH reached 6-7 the aqueouslayer was extracted with 10% EtOAc/DCM. The combined organic layerscontaining the ester were dried over Na₂SO₄. The aqueous layer wasacidified to pH 3-4 with 1N HCl and then extracted with 10% EtOAc/DCM toafford the acid. The ester layer was filtered, concentrated in vacuo toa white solid (460 mg, 71%). MS (ESI): mass calcd. C₆H₅FN₂O₂, 156.03;m/z found, 157.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.80 (s, 2H), 4.07 (s,3H).

Intermediate F, step b: 5-fluoropyrimidine-2-carbohydrazide

To a heterogeneous mixture of the product of Intermediate F, step a (456mg, 2.92 mmol) in EtOH (15 mL) was added hydrazine hydrate (0.29 mL,5.84 mmol). The solid started to go into solution and then a thick whiteprecipitate crashed out. After stirring for 1 h the reaction wascomplete and concentrated in vacuo to a white solid (487 mg, 100%). MS(ESI): mass calcd. C₅H₅FN₄O, 156.04; m/z found, 157.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃): 8.95-8.79 (m, 1H), 8.73 (s, 2H), 4.26-4.07 (m, 2H).

Intermediate G. 6-Methylpicolinohydrazide.

Intermediate G was made in a manner analogous to Intermediate Dsubstituting methyl 6-methylpicolinate formethylpyrimidine-2-carboxylate to provide the desired compound as awhite solid (493 mg, 99%). MS (ESI): mass calcd. C₇H₉N₃O, 151.07; m/zfound, 152.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.67 (s, 1H), 7.85 (t,J=7.7 Hz, 1H), 7.82-7.72 (m, 1H), 7.42 (dd, J=7.7, 0.6 Hz, 1H), 4.59 (s,2H), 2.56-2.51 (m, 3H).

Intermediate H: (1R,5S)-tert-Butyl2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

(1R,5S)-tert-Butyl 2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate wasprepared according to the procedures in Tetrahedron, 1992, 48, 4985.

Intermediate I: (1R,5S)-tert-butyl2-thioxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Intermediate I was made in a manner analogous to Intermediate Bsubstituting Intermediate H for Intermediate A to provide the desiredcompound as a white solid (742 mg, 91%). MS (ESI): mass calcd.C₁₁H₁₈N₂O₂S, 242.11; m/z found, 243.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.64 (s, 1H), 4.89 (s, 1H), 4.51 (s, 1H), 3.79 (s, 1H), 3.10 (dd,J=12.6, 2.7, 1H), 2.28-2.17 (m, 3H), 1.88-1.77 (m, 1H), 1.47 (s, 9H).

Intermediate J:(E/Z)-((1R,5S)-8-(tert-butoxycarbonvI)-3,8-diazabicyclo[3.2.1]octan-2-ylidene)(methyl)sulfoniumiodide

Intermediate J was made in a manner analogous to Intermediate Csubstituting Intermediate I for Intermediate B to provide the desiredcompound as a pale yellow foam (258 mg, 100%). MS (ESI): mass calcd.C₁₂H₂₀N₂O₂S, 256.12; m/z found, 257.1 [M+H]⁺.

Example 111-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

Example 1, step a:tert-butyl-3-(pyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine-11-carboxylate

To a round bottom flask was added Intermediate C (180 mg, 0.451 mmol),Intermediate D (69 mg, 0.497 mmol) and n-BuOH (2 mL). To this suspensionwas added KOtBu (63 mg, 0.564 mmol). After 30 min at room temperature,the mixture was heated at 120° C. for 24 h. The mixture was concentratedin vacuo and taken on to the next step without further purification. MS(ESI): mass calcd. C₁₇H₂₂N₆O₂, 342.18; m/z found, 343.1 [M+H]⁺.

Example 1, step b:3-(pyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

To a solution of the product of Example 1, step a (157 mg, 0.459 mmol)in DCM (2 mL) was added TFA (1 mL). The mixture was stirred for 2 h atroom temperature and then concentrated in vacuo.

The residue was chromatographed on SiO₂ eluting with 2M NH₃ in MeOH/DCMto afford the title compound as a colorless foam (68 mg, 61%). MS (ESI):mass calcd. C₁₂H₁₄N₆, 242.13; m/z found, 243.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.89 (d, J=4.9 Hz, 2H), 7.34 (t, J=4.9 Hz, 1H), 4.68-4.52 (m,3H), 3.72-3.66 (m, 1H), 2.13-1.62 (m, 6H), 1.33-1.17 (m, 1H).

Example 1, step c:11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

To a solution of the product of Example 1, step b (65 mg, 0.266 mmol) inDCM (3 mL) was added Intermediate E (68 mg, 0.280 mmol) followed by TEA(0.05 mL, 0.320 mmol). The reaction was stirred at room temperatureovernight and then loaded directly on a SiO₂ column eluting withIPA/EtOAc to afford the title compound (103 mg, 86%). MS (ESI): masscalcd. C₂₀H₁₆ClF₃N₆O, 448.10; m/z found, 448.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.95-8.86 (m, 2H), 7.83-7.76 (m, 1H), 7.61-7.34 (m, 3H),6.49-5.44 (m, 1H), 5.09-3.98 (m, 3H), 2.24-1.75 (m, 5H), 1.46-1.32 (m,1H).

Example 2(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 1 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) column and a mobile phase of 70% CO₂, 30%MeOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,2.94 min retention time). MS (ESI): mass calcd. C₂₀H₁₆ClF₃N₆O, 448.10;m/z found, 448.8 [M+H]⁺.

Example 3(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 1 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) column and a mobile phase of 70% CO₂, 30%MeOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,3.66 min retention time). MS (ESI): mass calcd. C₂₀H₁₆ClF₃N₆O, 448.10;m/z found, 448.8 [M+H]⁺.

Example 411-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting 4-fluorobenzohydrazide for Intermediate D. MS (ESI): masscalcd. C₂₂H₁₇ClF₄N₄O, 464.10; m/z found, 464.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.84-7.69 (m, 3H), 7.59-7.30 (m, 2H), 7.26-7.17 (m, 2H),5.51-5.44 (m, 1H), 5.07-3.94 (m, 3H), 2.23-1.74 (m, 5H), 1.35-1.23 (m,1H).

Example 5(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 4 performedusing a CHIRALPAK IA (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK IA (250×4.6 mm) column anda mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3% iPrNH₂over 7 minutes. (100% single enantiomer, 3.05 min retention time). MS(ESI): mass calcd. C₂₂H₁₇ClF₄N₄O, 464.10; m/z found, 464.9 [M+H]⁺.

Example 6(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 4 performedusing a CHIRALPAK IA (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK IA (250×4.6 mm) column anda mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3% iPrNH₂over 7 minutes. (98.8% single enantiomer, 3.31 min retention time). MS(ESI): mass calcd. C₂₂H₁₇ClF₄N₄O, 464.10; m/z found, 464.8 [M+H]⁺.

Example 711-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting thiazole-4-carboxylic acid hydrazide for Intermediate D. MS(ESI): mass calcd. C₁₉H₁₅ClF₃N₅OS, 453.06; m/z found, 453.9 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 8.95-8.84 (m, 1H), 8.31-8.25 (m, 1H), 7.82-7.77(m, 1H), 7.60-7.39 (m, 2H), 6.44-5.44 (m, 1H), 5.04-3.97 (m, 3H),2.23-1.73 (m, 5H), 1.47-1.32 (m, 1H).

Example 8(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 7 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) column and a mobile phase of 70% CO₂, 25%MeOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,5.10 min retention time). MS (ESI): mass calcd. C₁₉H₁₅ClF₃N₅O₅, 453.06;m/z found, 453.8 [M+H]⁺.

Example 9(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 7 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) column and a mobile phase of 70% CO₂, 25%MeOH containing 0.3% iPrNH₂ over 7 minutes. (99.3% single enantiomer,6.00 min retention time). MS (ESI): mass calcd. C₁₉H₁₅ClF₃N₅OS, 453.06;m/z found, 453.8 [M+H]⁺.

Example 1011-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting 5-fluoro-pyridine-2-carboxylic acid hydrazide forIntermediate D. MS (ESI): mass calcd. C₂₁H₁₆ClF₄N₅O, 465.10; m/z found,466.1 [M+H]⁺.

Example 11(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 10 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a Chiralpak AD-H (250×4.6 mm) columnand a mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 3.50 min retentiontime). MS (ESI): mass calcd. C₂₁H₁₆ClF₄N₅O, 465.10; m/z found, 465.8[M+H]⁺.

Example 12(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 10 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) columnand a mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 4.30 min retentiontime). MS (ESI): mass calcd. C₂₁H₁₆ClF₄N₅O, 465.10; m/z found, 465.8[M+H]⁺.

Example 1311-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting nicotinic acid hydrazide for Intermediate D. MS (ESI): masscalcd. C₂₁H₁₇ClF₃N₅O, 447.11; m/z found, 448.1 [M+H]⁺.

Example 14(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 13 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) columnand a mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 2.76 min retentiontime). MS (ESI): mass calcd. C₂₁H₁₇ClF₃N₅O, 447.11; m/z found, 447.8[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 9.06-8.90 (m, 1H), 8.82-8.72 (m, 1H),8.18-8.12 (m, 1H), 7.86-7.79 (m, 1H), 7.61-7.31 (m, 3H), 6.48-5.46 (m,1H), 5.10-3.99 (m, 3H), 2.26-1.72 (m, 5H), 1.39-1.19 (m, 1H).

Example 15(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 13 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) columnand a mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 3.79 min retentiontime). MS (ESI): mass calcd. C₂₁H₁₇ClF₃N₅O, 447.11; m/z found, 447.8[M+H]⁺.

Example 1611-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting Intermediate F for Intermediate D. MS (ESI): mass calcd.C₂₀H₁₅ClF₄N₆O, 466.09; m/z found, 467.1 [M+H]⁺.

Example 17(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 16 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) columnand a mobile phase of 60% CO₂, 20% EtOH, 20% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 2.41 min retentiontime). MS (ESI): mass calcd. C₂₀H₁₅ClF₄N₆O, 466.09; m/z found, 466.8[M+H]⁺.

Example 18(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 16 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% mixture of EtOH/iPrOH 50/50 (v/v). The enantiomeric purity wasconfirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) columnand a mobile phase of 60% CO₂, 20% EtOH, 20% iPrOH containing 0.3%iPrNH₂ over 7 minutes. (100% single enantiomer, 2.96 min retentiontime). MS (ESI): mass calcd. C₂₀H₁₅ClF₄N₆O, 466.09; m/z found, 466.8[M+H]⁺.

Example 1911-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting Intermediate F for Intermediate D, in Example 1 step a, andsubstituting 2,4 dichlorobenzoyl chloride for Intermediate E in Example1 step c. MS (ESI): mass calcd. C₁₉H₁₅Cl₂FN₆O, 432.07; m/z found, 433.1[M+H]⁺.

Example 20(6S*,10R*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 19 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% mixture of EtOH/iPrOH 50/50 (v/v) containing 0.3% iPrNH₂. Theenantiomeric purity was confirmed by analytical SFC using a CHIRALPAKAD-H (250×4.6 mm) column and a mobile phase of 60% CO₂, 20% EtOH, 20%iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,3.70 min retention time). MS (ESI): mass calcd. C₁₉H₁₅Cl₂FN₆O, 432.07;m/z found, 432.8 [M+H]⁺.

Example 21(6R*,10S*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 19 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% mixture of EtOH/iPrOH 50/50 (v/v) containing 0.3% iPrNH₂. Theenantiomeric purity was confirmed by analytical SFC using a CHIRALPAKAD-H (250×4.6 mm) column and a mobile phase of 60% CO₂, 20% EtOH, 20%iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,5.39 min retention time). MS (ESI): mass calcd. C₁₉H₁₅Cl₂FN₆O, 432.07;m/z found, 432.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.83-8.71 (m, 2H),7.55-7.28 (m, 2H), 7.22-6.99 (m, 1H), 6.46-5.42 (m, 1H), 5.12-4.03 (m,3H), 2.25-1.74 (m, 5H), 1.43-1.24 (m, 1H).

Example 2211-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting Intermediate G for Intermediate D. MS (ESI): mass calcd.C₂₂H₁₉ClF₃N₅O, 461.12; m/z found, 462.1 [M+H]⁺.

Example 23(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 22 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 75% CO₂, 25%iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,3.95 min retention time). MS (ESI): mass calcd. C₂₂H₁₉ClF₃N₅O, 461.12;m/z found, 461.8 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.22-8.11 (m, 1H),7.83-7.76 (m, 1H), 7.76-7.69 (m, 1H), 7.61-7.27 (m, 2H), 7.25-7.16 (m,1H), 6.45-5.43 (m, 1H), 5.06-4.00 (m, 3H), 2.65-2.50 (m, 3H), 2.24-1.72(m, 5H), 1.45-1.31 (m, 1H).

Example 24(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 22 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% iPrOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 75% CO₂, 25%iPrOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,4.87 min retention time). MS (ESI): mass calcd. C₂₂H₁₉ClF₃N₅O, 461.12;m/z found, 461.8 [M+H]⁺.

Example 2511-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting 4-methoxy-pyridine-2-carboxylic acid hydrazide forIntermediate D. MS (ESI): mass calcd. C₂₂H₁₉ClF₃N₅O₂, 477.12; m/z found,478.1 [M+H]⁺.

Example 26(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 25 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 80% CO₂,20% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 75% CO₂, 25% MeOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 3.30 minretention time). MS (ESI): mass calcd. C₂₂H₁₉ClF₃N₅O₂, 477.12; m/zfound, 477.8 [M+H]⁺.

Example 27(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 25 performedusing a CHIRALCEL OD-H (250×20 mm) column and a mobile phase of 80% CO₂,20% MeOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALCEL OD-H (250×4.6 mm) and a mobile phase of 75% CO₂, 25% MeOHcontaining 0.3% iPrNH₂ over 7 minutes. (98.9% single enantiomer, 4.04min retention time). MS (ESI): mass calcd. C₂₂H₁₉ClF₃N₅O₂, 477.12; m/zfound, 477.8 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.48-8.31 (m, 1H),7.95-7.85 (m, 1H), 7.84-7.75 (m, 1H), 7.62-7.25 (m, 2H), 6.93-6.83 (m,1H), 6.46-5.41 (m, 1H), 5.07-3.96 (m, 3H), 3.97-3.90 (m, 3H), 2.26-1.72(m, 5H), 1.47-1.29 (m, 1H).

Example 283-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting 5-chloro-2-pyridinecarbohydrazide for Intermediate D. MS(ESI): mass calcd. C₂₁H₁₆Cl₂F₃N₅O, 481.07; m/z found, 482.1 [M+H]⁺.

Example 29(6S*,10R*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 28 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 60% CO₂, 40%EtOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,2.51 min retention time). MS (ESI): mass calcd. C₂₁H₁₆Cl₂F₃N₅O, 481.07;m/z found, 481.7 [M+H]⁺.

Example 30(6R*,10S*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 28 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 60% CO₂,40% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 60% CO₂, 40%EtOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,3.59 min retention time). MS (ESI): mass calcd. C₂₁H₁₆Cl₂F₃N₅O, 481.07;m/z found, 481.7 [M+H]⁺.

Example 3111-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 1substituting 2-picolinyl hydrazide for Intermediate D. MS (ESI): masscalcd. C₂₁H₁₇ClF₃N₅O, 447.11; m/z found, 448.1 [M+H]⁺.

Example 32(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 31 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 75% CO₂, 25%EtOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,4.05 min retention time). MS (ESI): mass calcd. C₂₁H₁₇ClF₃N₅O, 447.11;m/z found, 447.7 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.69-8.55 (m, 1H),8.42-8.32 (m, 1H), 7.88-7.77 (m, 2H), 7.60-7.27 (m, 3H), 6.45-5.43 (m,1H), 5.06-3.98 (m, 3H), 2.23-1.96 (m, 3H), 1.92-1.73 (m, 2H), 1.47-1.32(m, 1H).

Example 33(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 31 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 75% CO₂,25% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 75% CO₂, 25% EtOHcontaining 0.3% iPrNH₂ over 7 minutes. (99.2% single enantiomer, 4.79min retention time). MS (ESI): mass calcd. C₂₁H₁₇ClF₃N₅O, 447.11; m/zfound, 447.7 [M+H]⁺.

Example 3411-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]-carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

Example 34, step a: tert-butyl3-(thiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine-11-carboxylate

To a round bottom flask was added Intermediate C (305 mg, 0.766 mmol),2-thiophenecarboxylic acid hydrazide (122 mg, 0.843 mmol) and EtOH (3mL). This heterogeneous mixture was stirred at room temperature for 60h. To this suspension was added KOtBu (107 mg, 0.958 mmol). After 30 minat room temperature, the mixture was heated at 100° C. for 15 h. Themixture was concentrated in vacuo and chromatographed on SiO₂ elutingwith EtOAc/Hex to afford the desired compound (204 mg, 77%). MS (ESI):mass calcd. C₁₇H₂₂N₄O₂S, 346.15; m/z found, 347.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.55-7.45 (m, 2H), 7.18 (dd, J=5.1, 3.7 Hz, 1H), 5.79-5.54(m, 1H), 4.98-4.71 (m, 1H), 4.43-4.32 (m, 1H), 4.09 (d, J=12.3 Hz, 1H),2.05-1.88 (m, 3H), 1.80-1.65 (m, 2H), 1.48 (s, 9H), 1.30-1.18 (m, 1H).

Example 34, step b:3-(thiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

To a solution of the product of Example 34, step a (201 mg, 0.582 mmol)in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 2 h atroom temperature and then concentrated in vacuo. The residue waschromatographed on SiO₂ eluting with 2 M NH₃ in MeOH/DCM to afford thetitle compound as a colorless foam (140 mg, 98%). MS (ESI): mass calcd.C₁₂H₁₄N₄S, 246.09; m/z found, 247.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.53 (dd, J=3.7, 1.1 Hz, 1H), 7.48 (dd, J=5.1, 1.1 Hz, 1H), 7.17 (dd,J=5.1, 3.7 Hz, 1H), 4.58 (t, J=3.4 Hz, 1H), 4.36-4.29 (m, 1H), 4.10 (d,J=12.4 Hz, 1H), 3.76-3.70 (m, 1H), 2.08-1.95 (m, 3H), 1.75-1.63 (m, 2H),1.29-1.16 (m, 1H).

Example 34, step c:11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

To a solution of the product of Example 34, step b (138 mg, 0.560 mmol)in DCM (6 mL) was added3-chloro-2-(trifluoromethyl)-4-pyridinecarboxylic acid (139 mg, 0.616mmol) followed by HOBt (53 mg, 0.392 mmol), EDCl (161 mg, 0.840 mmol)and TEA (0.16 mL, 0.320 mmol). The reaction was stirred at roomtemperature overnight and then loaded directly on a SiO₂ column elutingwith EtOAc/Hex to afford the title compound (202 mg, 79%). MS (ESI):mass calcd. C₁₉H₁₅ClF₃N₅OS, 453.06; m/z found, 454.1 [M+H]⁺.

Example 35(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 34 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) column and a mobile phase of 70% CO₂, 30%EtOH containing 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer,3.55 min retention time). MS (ESI): mass calcd. C₁₉H₁₅ClF₃N₅OS, 453.06;m/z found, 453.7 [M+H]⁺.

Example 36(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 34 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 70% CO₂,30% EtOH. The enantiomeric purity was confirmed by analytical SFC usinga CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 30% EtOHcontaining 0.3% iPrNH₂ over 7 minutes. (100% single enantiomer, 4.44 minretention time). MS (ESI): mass calcd. C₁₉H₁₅ClF₃N₅OS, 453.06; m/zfound, 453.7 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.75-8.60 (m, 1H),7.59-7.45 (m, 3H), 7.24-7.12 (m, 1H), 5.53-5.46 (m, 1H), 4.95 (s, 1H),4.60-4.47 (m, 1H), 4.31-3.98 (m, 1H), 2.24-1.77 (m, 5H), 1.44-1.29 (m,1H).

Example 3711-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound was prepared in a manner analogous to Example 34substituting 5-methyl-2-thiophenecarboxylic acid hydrazide for2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₂₀H₁₇ClF₃N₅OS, 467.08; m/z found, 468.1 [M+H]⁺.

Example 38(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 37 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 65% CO₂,35% EtOH containing 0.3% iPrNH₂. The enantiomeric purity was confirmedby analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) column and amobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7 minutes.(100% single enantiomer, 3.41 min retention time). MS (ESI): mass calcd.C₂₀H₁₇ClF₃N₅OS, 467.08; m/z found, 467.7 [M+H]⁺.

Example 39(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]-carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine

The title compound, absolute configuration unknown, was obtained as asingle enantiomer by Chiral SFC purification of Example 37 performedusing a CHIRALPAK AD-H (250×20 mm) column and a mobile phase of 65% CO₂,35% EtOH containing 0.3% iPrNH₂. The enantiomeric purity was confirmedby analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) column and amobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7 minutes.(100% single enantiomer, 4.99 min retention time). MS (ESI): mass calcd.C₂₀H₁₇ClF₃N₅OS, 467.08; m/z found, 467.7 [M+H]⁺.

Example 40(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

Example 40, step a:(6S,9R)-tert-butyl-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine-10-carboxylate

To a round bottom flask was added Intermediate I (120 mg, 0.494 mmol),4-fluorobenzhydrazide (119 mg, 0.742 mmol) and n-BuOH (2 mL). Themixture was heated at 140° C. for 72 h and then concentrated in vacuoand taken on to the next step without further purification. MS (ESI):mass calcd. C₁₈H₂₁FN₄O₂, 344.16; m/z found, 345.2 [M+H]⁺.

Example 40, step b:(6S,9R)-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

To a solution of the product of Example 40, step a (170 mg, 0.494 mmol)in DCM (5 mL) was added TFA (2 mL). The mixture was stirred for 2 h atroom temperature and then concentrated in vacuo. The residue waschromatographed on SiO₂ eluting with 2M NH₃ in MeOH/DCM to afford thetitle compound as a white solid (114 mg, 94%). MS (ESI): mass calcd.C₁₃H₁₃FN₄, 244.11; m/z found, 245.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.74-7.67 (m, 2H), 7.21-7.14 (m, 2H), 4.81-4.77 (m, 1H), 4.24-4.18 (m,1H), 4.09-4.04 (m, 1H), 3.85-3.81 (m, 1H), 2.28-2.10 (m, 3H), 1.72-1.65(m, 1H).

Example 40, step c:(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

To a solution of the product of Example 40, step b (111 mg, 0.453 mmol)in DCM (3 mL) was added Intermediate E (116 mg, 0.476 mmol) followed byTEA (0.08 mL, 0.544 mmol). The reaction was stirred at room temperatureovernight and then loaded directly on a SiO₂ column eluting withEtOAc/Hex to afford the title compound (186 mg, 91%). MS (ESI): masscalcd. C₂₁H₁₅ClF₄N₄O, 450.09; m/z found, 451.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.86-7.29 (m, 5H), 7.26-7.14 (m, 2H), 5.43-5.32 (m, 1H),5.02-4.92 (m, 1H), 4.71-4.55 (m, 1H), 4.07-3.79 (m, 1H), 2.60-2.18 (m,3H), 1.92-1.77 (m, 1H).

Example 41(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting 2-picolinyl hydrazide for 4-fluorobenzhydrazide. MS (ESI):mass calcd. C₂₀H₁₅ClF₃N₅O, 433.09; m/z found, 434.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.68-8.51 (m, 1H), 8.40-8.29 (m, 1H), 7.88-7.75 (m, 2H),7.56-7.27 (m, 3H), 5.43-5.31 (m, 1H), 5.03-4.49 (m, 3H), 2.60-2.19 (m,3H), 2.01-1.85 (m, 1H).

Example 42(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting 2-pyrazinecarbohydrazide for 4-fluorobenzhydrazide. MS(ESI): mass calcd. C₁₉H₁₄ClF₃N₆O, 434.09; m/z found, 435.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 9.67-9.53 (m, 1H), 8.69-8.46 (m, 2H), 7.85-7.75(m, 1H), 7.60-7.27 (m, 2H), 5.44-5.31 (m, 1H), 5.04-4.45 (m, 3H),2.62-2.20 (m, 3H), 2.01-1.86 (m, 1H).

Example 43(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

Example 43, step a: (6S,9R)-tert-butyl3-(pyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine-10-carboxylate

The title compound was prepared in a manner analogous to Example 40 stepa, substituting 2-picolinyl hydrazide for 4-fluorobenzhydrazide. MS(ESI): mass calcd. C₁₇H₂₁N₅O₂, 327.17; m/z found, 328.2 [M+H]⁺.

Example 43, step b:(6S,9R)-3-(pyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40 stepb, substituting the product of Example 43 step a, for the product ofExample 40, step a. MS (ESI): mass calcd. C₁₂H₁₃N₅, 227.12; m/z found,228.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.61-8.56 (m, 1H), 8.31-8.24 (m,1H), 7.82-7.75 (m, 1H), 7.33-7.27 (m, 1H), 4.86-4.78 (m, 1H), 4.56-4.45(m, 2H), 4.13-4.04 (m, 1H), 2.32-2.12 (m, 3H), 1.82-1.73 (m, 1H).

Example 43, step c:(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 34 stepc, substituting the product of Example 43 step b, for the product ofExample 34 step b, and 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acidfor 3-chloro-2-(trifluoromethyl)-4-pyridinecarboxylic acid. MS (ESI):mass calcd. C₂₀H₁₄ClF₄N₅O, 451.08; m/z found, 452.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.67-8.52 (m, 1H), 8.39-8.29 (m, 1H), 7.89-7.78 (m, 1H),7.55-7.28 (m, 2H), 7.25-7.10 (m, 1H), 5.39-5.27 (m, 1H), 5.01-4.54 (m,3H), 2.58-2.20 (m, 3H), 2.02-1.88 (m, 1H).

Example 44(6S,9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 43substituting 2-methyl-3-(trifluoromethyl)benzoic acid for and2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid. MS (ESI): mass calcd.C₂₁H₁₈F₃N₅O, 413.15; m/z found, 414.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) d8.68-8.53 (m, 1H), 8.41-8.31 (m, 1H), 7.88-7.81 (m, 1H), 7.75-7.67 (m,1H), 7.45-7.29 (m, 3H), 6.22 (s, 0.2H), 5.44-5.31 (m, 0.8H), 5.02-4.92(m, 0.8H), 4.86-4.79 (m, 0.8H), 4.79-4.72 (m, 0.8H), 4.61-4.54 (m,0.2H), 4.39-4.32 (m, 0.2H), 4.21-4.13 (m, 0.2H), 2.69-1.79 (m, 7H).

Example 45(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting 5-fluoro-pyridine-2-carboxylic acid hydrazide for4-fluorobenzhydrazide. MS (ESI): mass calcd. C₂₀H₁₄ClF₄N₅O, 451.08; m/zfound, 452.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.56-8.31 (m, 2H),7.84-7.74 (m, 1H), 7.60-7.28 (m, 3H), 6.24-6.18 (m, 0.25H), 5.43-5.31(m, 0.75H), 5.03-4.16 (m, 3H), 2.60-2.19 (m, 3H), 2.01-1.85 (m, 1H).

Example 46(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting Intermediate D for 4-fluorobenzhydrazide. MS (ESI): masscalcd. C₁₉H₁₄ClF₃N₆O, 434.09; m/z found, 435.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.93-8.83 (m, 2H), 7.84-7.76 (m, 1H), 7.58-7.27 (m, 3H),6.28-6.20 (m, 0.2H), 5.45-5.32 (m, 0.8H), 5.01-4.18 (m, 3H), 2.60-2.22(m, 3H), 2.01-1.84 (m, 1H).

Example 47(6S,9R)-10-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 43substituting 2-pyrazinecarbohydrazide for 2-picolinyl hydrazide inExample 43 step a, and 2,3-dichloro-4-fluorobenzoic acid for2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid in Example 43 step c.MS (ESI): mass calcd. C₁₈H₁₃Cl₂FN₆O, 418.05; m/z found, 419.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 9.63-9.56 (m, 1H), 8.67-8.49 (m, 2H), 7.26-6.92(m, 2H), 5.37-5.31 (m, 1H), 5.06-4.19 (m, 3H), 2.59-2.19 (m, 3H),2.00-1.85 (m, 1H).

Example 48(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting nicotinic acid hydrazide for 4-fluorobenzhydrazide. MS(ESI): mass calcd. C₂₀H₁₅ClF₃N₅O, 433.09; m/z found, 434.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 9.04-8.86 (m, 1H), 8.82-8.70 (m, 1H), 8.19-8.07(m, 1H), 7.86-7.77 (m, 1H), 7.60-7.31 (m, 3H), 5.49-5.31 (m, 1H),5.06-3.86 (m, 3H), 2.65-2.20 (m, 3H), 1.94-1.77 (m, 1H).

Example 49(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting thiazole-4-carboxylic acid hydrazide for4-fluorobenzhydrazide. MS (ESI): mass calcd. C₁₈H₁₃ClF₃N₅OS, 439.05; m/zfound, 440.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.96-8.80 (m, 1H),8.29-8.23 (m, 1H), 7.83-7.76 (m, 1H), 7.55-7.27 (m, 2H), 5.42-5.31 (m,1H), 4.99-4.16 (m, 3H), 2.59-2.19 (m, 3H), 2.01-1.85 (m, 1H).

Example 50(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting Intermediate F for 4-fluorobenzhydrazide. MS (ESI): masscalcd. C₁₉H₁₃ClF₄N₆O, 452.08; m/z found, 453.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.81-8.69 (m, 2H), 7.84-7.76 (m, 1H), 7.57-7.27 (m, 2H),5.43-5.33 (m, 1H), 5.02-4.18 (m, 3H), 2.63-2.21 (m, 3H), 2.00-1.84 (m,1H).

Example 51(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(3-methyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 40substituting 3-methyl-1H-pyrazole-5-carbohydrazide for4-fluorobenzhydrazide. MS (ESI): mass calcd. C₁₉H₁₆ClF₃N₆O, 436.10; m/zfound, 437.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.82-7.75 (m, 1H),7.56-7.27 (m, 2H), 6.77-6.71 (m, 1H), 5.44-5.32 (m, 1H), 5.00-4.90 (m,1H), 4.75-4.08 (m, 2H), 2.59-2.18 (m, 6H), 2.01-1.83 (m, 1H).

Example 52(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 43substituting thiazole-4-carboxylic acid hydrazide for 2-picolinylhydrazide in Example 43. MS (ESI): mass calcd. C₁₈H₁₂ClF₄N₅OS, 457.04;m/z found, 458.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.94-8.82 (m, 1H),8.29-8.23 (m, 1H), 7.57-7.41 (m, 1H), 7.26-7.12 (m, 1H), 5.39-5.31 (m,1H), 4.98-4.16 (m, 3H), 2.60-2.19 (m, 3H), 2.02-1.87 (m, 1H).

Example 53(6S,9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 43substituting thiazole-4-carboxylic acid hydrazide for 2-picolinylhydrazide in Example 43 step a, and 2-methyl-3-(trifluoromethyl)benzoicacid for 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid in Example43, step c. MS (ESI): mass calcd. C₁₉H₁₆F₃N₅OS, 419.10; m/z found, 420.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.93-8.83 (m, 1H), 8.30-8.20 (m, 1H),7.75-7.67 (m, 1H), 7.45-7.27 (m, 2H), 5.42-5.32 (m, 1H), 5.00-4.11 (m,3H), 2.64-1.84 (m, 7H).

Example 54(6S,9R)-10-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 43substituting thiazole-4-carboxylic acid hydrazide for 2-picolinylhydrazide in Example 43 step a, and 2,4-dichloro-3-fluorobenzoic acidfor 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid in Example 43,step c. MS (ESI): mass calcd. C₁₇H₁₂Cl₂FN₅OS, 423.01; m/z found, 424.0[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.92-8.81 (m, 1H), 8.28-8.23 (m, 1H),7.46-7.32 (m, 1H), 7.13-6.89 (m, 1H), 5.36-5.31 (m, 1H), 5.02-4.19 (m,3H), 2.56-2.18 (m, 3H), 1.99-1.86 (m, 1H).

Example 55(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

Example 55, step a: tert-butyl(6S,9R)-3-(5-chlorothiophen-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine-10-carboxylate

To a round bottom flask was added Intermediate J (258 mg, 0.673 mmol),5-chloro-2-thiophenecarboxylic acid hydrazide (133 mg, 0.740 mmol) andn-BuOH (3 mL). This heterogeneous mixture was stirred at roomtemperature for 4 h. To this suspension was added KOtBu (94 mg, 0.841mmol). After 30 min at room temperature, the mixture was heated at 100°C. for 15 h. The mixture was concentrated in vacuo and chromatographedon SiO₂ eluting with EtOAc/Hex to afford the desired compound (218 mg,88%). MS (ESI): mass calcd. C₁₆H₁₉ClN₄O₂S, 366.09; m/z found, 367.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.20 (d, J=4.0 Hz, 1H), 6.97 (d, J=4.0Hz, 1H), 5.51-5.40 (m, 1H), 4.85-4.72 (m, 1H), 4.45-4.30 (m, 1H),3.94-3.86 (m, 1H), 2.44-2.35 (m, 1H), 2.31-2.22 (m, 1H), 2.17-2.09 (m,1H), 1.78-1.70 (m, 1H), 1.44 (s, 9H).

Example 55, step b:(6S,9R)-3-(5-Chlorothiophen-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

To a solution of the product of Example 55 step a (215 mg, 0.586 mmol)in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 2 h atroom temperature and then concentrated in vacuo. The residue waschromatographed on SiO₂ eluting with 2M NH₃ in MeOH/DCM to afford thetitle compound as a colorless foam (127 mg, 81%). MS (ESI): mass calcd.C₁₁H₁₁ClN₄S, 266.04; m/z found, 267.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):7.16 (d, J=4.0 Hz, 1H), 6.93 (d, J=4.0 Hz, 1H), 4.76-4.72 (m, 1H),4.22-4.16 (m, 1H), 4.11-4.06 (m, 1H), 3.92-3.87 (m, 1H), 2.30-2.09 (m,3H), 1.74-1.66 (m, 2H).

Example 55, step c:(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

To a solution of the product of Example 55 step b (50 mg, 0.186 mmol) inDCM (2 mL) was added Intermediate E (47 mg, 0.195 mmol) followed by TEA(0.03 mL, 0.223 mmol). The reaction was stirred at room temperatureovernight and then loaded directly on a SiO₂ column eluting withIPA/EtOAc to afford the title compound (82 mg, 93%). MS (ESI): masscalcd. C₁₉H₁₃Cl₂F₃N₄OS, 472.01; m/z found, 473.0 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.84-7.77 (m, 1H), 7.58-7.27 (m, 2H), 7.25-7.15 (m, 1H),7.03-6.93 (m, 1H), 5.44-5.34 (m, 1H), 5.00-3.90 (m, 3H), 2.64-2.19 (m,3H), 1.97-1.83 (m, 1H).

Example 56(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methyl-1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting 2-methyl-thiazole-4-carboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₉H₁₅ClF₃N₅OS, 453.06; m/z found, 454.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.04-7.98 (m, 1H), 7.83-7.76 (m, 1H), 7.56-7.27 (m, 2H),5.40-4.15 (m, 4H), 2.81-2.67 (m, 3H), 2.59-2.17 (m, 3H), 2.01-1.85 (m,1H).

Example 57(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting thiazole-5-carboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₈H₁₃ClF₃N₅OS, 439.05; m/z found, 439.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.99-8.90 (m, 1H), 8.31-8.13 (m, 1H), 7.86-7.77 (m, 1H),7.57-7.28 (m, 2H), 5.47-3.95 (m, 4H), 2.65-2.21 (m, 3H), 1.99-1.84 (m,1H).

Example 58(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting 3-thiophenecarboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₉H₁₄ClF₃N₄OS, 438.05; m/z found, 438.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.84-7.28 (m, 6H), 5.46-5.31 (m, 1H), 5.02-4.91 (m, 1H),4.74-4.55 (m, 1H), 4.26-3.87 (m, 1H), 2.61-2.19 (m, 3H), 1.95-1.81 (m,1H).

Example 59(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methyl-1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting 3-methylthiazole-5-carboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₉H₁₅ClF₃N₅OS, 453.06; m/z found, 453.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 8.95-8.83 (m, 1H), 7.85-7.78 (m, 1H), 7.56-7.29 (m, 2H),5.44-5.29 (m, 1H), 5.05-4.89 (m, 1H), 4.53-4.18 (m, 1H), 4.00-3.82 (m,1H), 2.70 (br s, 3H), 2.61-2.21 (m, 3H), 1.95-1.80 (m, 1H).

Example 60(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[3-chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

To a solution of(6S,9R)-3-(5-chlorothiophen-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine(Example 55, step b) (35 mg, 0.132 mmol) in DCM (2 mL) was added3-chloro-2-(trifluoromethyl)-4-pyridinecarboxylic acid (30 mg, 0.132mmol) followed by HOBt (12 mg, 0.09 mmol), EDCl (38 mg, 0.197 mmol) andTEA (0.04 mL, 0.263 mmol). The reaction was stirred at room temperatureovernight and then loaded directly on a SiO₂ column eluting withIPA/EtOAc to afford the title compound (53 mg, 85%). MS (ESI): masscalcd. C₁₈H₁₂Cl₂F₃N₅OS, 473.01; m/z found, 473.8 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 8.75-8.59 (m, 1H), 7.68-7.30 (m, 1H), 7.26-7.13 (m, 1H),7.03-6.92 (m, 1H), 5.46-5.31 (m, 1H), 4.98-4.87 (m, 1H), 4.65-4.50 (m,1H), 4.25-3.94 (m, 1H), 2.63-2.23 (m, 3H), 2.00-1.86 (m, 1H).

Example 61(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting 2-thiophenecarboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₉H₁₄ClF₃N₄OS, 438.05; m/z found, 438.9 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): 7.84-7.76 (m, 1H), 7.58-7.28 (m, 4H), 7.21-7.13 (m, 1H),5.46-5.34 (m, 1H), 5.00-3.94 (m, 3H), 2.63-2.19 (m, 3H), 1.98-1.83 (m,1H).

Example 62(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1H-pyrrol-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine

The title compound was prepared in a manner analogous to Example 55substituting pyrrole-2-carboxylic acid hydrazide for5-chloro-2-thiophenecarboxylic acid hydrazide. MS (ESI): mass calcd.C₁₉H₁₅ClF₃N₅O, 421.09; m/z found, 422.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):11.05-10.57 (m, 1H), 7.84-7.74 (m, 1H), 7.59-7.27 (m, 2H), 7.08-7.02 (m,1H), 6.57-6.13 (m, 2H), 5.47-3.80 (m, 4H), 2.62-2.14 (m, 3H), 2.00-1.81(m, 1H).

Examples 63 to 192 are made in accordance with the synthetic schemes,and in light of the specific examples, provided above Example 63(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(3-(Pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 64(2-fluoro-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 65(3-chloro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 66((2-methyl-3-(trifluoromethyl)phenyl)(3-(Pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 67(3-methyl-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 68(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 69(2,4-dichloro-3-fluorophenyl)(3-(Pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 70(2,3-dichloro-4-fluorophenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 71(2-chloro-3-(trifluoromethyl)phenyl)(3-(3-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 72(2-chloro-3-(trifluoromethyl)phenyl)(3-(3,5-difluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 73((2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-6-methylpyridin-2-Y1)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 74(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 75(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 76(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(difluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 77(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-hydroxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 78(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-ethoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 79(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-isopropoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 80(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 81(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 82(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 83(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 84(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone

Example 85(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 86(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 87(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 88(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 89(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 90(2,3-dichlorophenyl)((6R,10S)-3-(Pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 91(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 92(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 93(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 94(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 95(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 96(2,3-dichlorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 97(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 98(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 99U6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 100(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 101(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 102(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 103(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 104(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 105((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone

Example 106(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 107(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 108(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 109(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 110(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 111((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 112(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 113(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 114(2,3-dichlorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 115(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 116(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 117(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 118(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 119(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 120(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 121(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 122(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 123(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 124(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 125(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 126(2,3-dichlorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 127(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 128(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 129((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 130(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 131(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 132(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 133((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-chloro-3-1-trifluoromethyl)phenyl)methanone

Example 134((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichloro-4-fluorophenyl)methanone

Example 135((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 136((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone

Example 137((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-itrifluoromethyl)pyridin-4-yOrnethanone

Example 138((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichlorophenyl)methanone

Example 139(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 140(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 141((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 142(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 143(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 144(2,3-dichlorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 145(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 146(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 147((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 148(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 149(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 150(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 151(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 152(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 153((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 154((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-1-trifluoromethyl)phenyl)methanone

Example 155((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone

Example 156(2,3-dichlorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 157(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 158(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 159((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-1-trifluoromethyl)phenyl)methanone

Example 160(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 161((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-itrifluoromethyl)pyridin-4-yOrnethanone

Example 162(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 163(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 164(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 165(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 166(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 167(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 168(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 169(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 170(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 171(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 172(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 173(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 174(2,3-dichlorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 175(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 176(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 177((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone

Example 178(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 179(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 180(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 181(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 182(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 183(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 184(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 185(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 186(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 187(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 188(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 189(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 190(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 191(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Example 192(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone

Pharmacological Examples P2X7 Antagonism in Human Peripheral BloodMononuclear Cells (PBMCs) And Mouse/Human Whole Blood

Human blood was collected using a blood donor program. PBMCs wereisolated from blood using a Ficoll density gradient technique. Briefly,blood was laid on Ficoll solution and centrifuged at RT for 20 minutesat 2000 rpm. The buffy layer (between red blood cells and plasma) wascarefully collected by aspiration, washed with PBS and centrifuged againat 1500 rpm for 15 minutes. The resulting cell pellet was washed andplated on 96 well-plates for experiments. For the Mouse/Human WholeBlood experiments, 150 μl of either mouse or human blood was platted on96 well-plates. Lipopolysaccharide (LPS) (30 ng/ml) was added to eachwell and incubated for 1 hour. Test compounds were then added andincubated for 30 minutes. The P2X7 agonist, 2′(3′)—O-(4-benzoylbenzoyl)adenosine 5′ triphosphate (Bz-ATP) was then added at a finalconcentration of 0.5 mM (PBMC) or 1 mM (blood). Cells were incubated foran additional 1.5 hours. At that point, supernatant was collected andstored for IL-113 assay using manufacturer's protocol for enzyme-linkedimmunosorbent assay (ELISA). Data was expressed as percent control,where control is defined as the difference in IL-1β release inLPS+Bz-ATP samples and LPS only samples. Data was plotted as response(')/0 control) versus concentration to generate IC₅₀ values. In Table 2,this data is represented by PBMC P2X7 and blood P2X7 IC₅₀.

P2X7 Antagonism in Recombinant hP2X7 Cells: (a) Ca²⁺ Flux (b)Radioligand Binding

(A) Ca²⁺flux: 1321N1 cells expressing the recombinant human, rat ormouse P2X7 channel was cultured in HyQ DME/(HyClone/Dulbecco's ModifiedEagle Medium) high glucose supplemented with 10% Fetal Bovine Serum(FBS) and appropriate selection marker. Cells were seeded at a densityof 25000 cells/well (96-well clear bottom black walled plates) in 100 μlvolume/well. On the day of the experiment, cell plates were washed withassay buffer, containing (in mM): 130 NaCl, 2 KCl, 1 CaCl₂, 1 MgCl₂, 10HEPES, 5 glucose; pH 7.40 and 300 mOs. After the wash, cells were loadedwith the Calcium-4 dye (Molecular Device) and incubated in the dark for60 minutes. Test compounds were prepared at 250× the test concentrationin neat DMSO. Intermediate 96-well compound plates were prepared bytransferring 1.2 μL of the compound into 300 μL of assay buffer. Afurther 3× dilution occurred when transferring 50 μL/well of thecompound plate to 100 μL/well in the cell plate. Cells were incubatedwith test compounds and dye for 30 minutes. Calcium dye fluorescence wasmonitored in FLIPR as the cells were challenged by adding 50 μL/well ofBzATP (final concentration is 250 μM BzATP (human and rat) or 600 μM(mouse)). The fluorescence change was measured 180 seconds after addingthe agonist. Peak fluorescence was plotted as a function of testconcentration and the resultant IC₅₀ is shown in Table 2

(B) Radioligand binding: human or rat P2×7-1321N1 cells were collectedand frozen @-80° C. On the day of the experiment, cell membranepreparations were made according to standard published methods. Thetotal assay volume was 100 μl:10 μl compound (10×)+(b) 40 μl tracer(2.5×)+50 μl membrane (2×). The tracer used for the assay was tritiatedA-804598. The compound can be prepared as described in the literature.(Donnelly-Roberts, D. Neuropharmacology 2008, 56 (1), 223-229.)Compounds, tracer and membranes were incubated for 1 hour @ 4° C. Theassay was terminated by filtration (GF/B filters pre-soaked with 0.3%PEI) and washed with washing buffer (Tris-HCl 50 mM). The IC₅₀ generatedin the binding assay was corrected for tracer concentration and affinityof the tracer to derive at the affinity (K_(i)) of the test compounds.

TABLE 2 P2X7 activity of compounds of Formula (I) in a panel of in-vitroassays Human PBMC P2X7 P2X7 FLIPR FLIPR whole Exam- 10 μM human rat(human) (rat) blood ple (% Ki Ki IC₅₀ IC₅₀ IC₅₀ No. control) (μM) (μM)(μM) (μM) (μM) 1 11.0 0.0501 NT 0.0038 0.0045 NT 2 45.7 NTNT >10     >10 NT 3 8.9 0.0398 0.0040 0.0096 0.0081 NT 4 6.1 0.0200 NT0.0953 0.1327 NT 5 −4.4 0.0126 NT 0.0634 0.0147 NT 6 5.8 NT NT 2.29622.3227 NT 7 9.9 0.0126 NT 0.0077 0.0157 NT 8 7.3 0.0100 0.0013 0.00970.0025 NT 9 7.3 0.3981 NT 0.4819 0.1803 NT 11 38.9 NT NT 5.6885 14.8252NT 12 −0.8 0.0126 0.0034 0.0133 0.0366 0.1259 14 2.4 0.0174 NT 0.01000.0082 NT 15 89.8 NT NT NT NT NT 17 84.2 NT NT NT NT NT 18 −9.0 0.0138NT 0.0011 0.0044 NT 20 104.2 NT NT NT NT NT 21 −2.1 0.0501 NT 0.09483.3497 NT 23 8.0 0.0240 0.0050 0.0404 0.0560 NT 24 32.7 NT NT 3.6983 >10NT 26 9.2 0.0304 0.0040 0.0100 0.0014 0.0398 27 4.8 NT NT 1.9055 1.5417NT 29 91.4 NT NT NT NT NT 30 1.4 0.0355 NT 0.1183 2.7733 NT 32 94.5 NTNT NT NT NT 33 −1.0 0.0105 0.0032 0.0134 0.0113 0.0437 35 82.2 NT NT NTNT NT 36 −1.2 0.0107 NT 0.0365 0.3381 NT 38 101.0 NT NT NT NT NT 39 5.80.0251 NT 0.0511 0.0798 NT 40 −1.3 0.0219 0.0355 0.0126 10.0000 NT 41−20.0 0.0126 0.0079 0.0063 1.5849 NT 42 −21.3 0.0126 0.0079 0.02000.2512 NT 43 −18.6 0.0129 0.0138 0.0200 3.9811 NT 44 7.9 0.0126 0.01260.0077 8.4918 NT 45 6.5 0.0126 0.0316 0.0131 15.8125 NT 46 10.0 0.01580.0063 0.0152 0.2529 NT 47 0.0 0.0100 0.0063 0.0203 1.9231 NT 48 −0.60.0398 0.0158 0.0132 2.9174 NT 49 1.1 0.0200 0.0040 0.0050 0.0135 NT 5010.4 0.0158 0.0100 0.0104 6.7764 NT 51 −0.8 0.0398 0.0079 0.0144 4.1020NT 52 7.7 0.0316 0.0063 0.0102 0.1312 NT 53 4.0 0.0126 0.0079 0.00313.8637 NT 54 9.7 0.0251 0.0079 0.0061 8.9125 NT 55 15.3 0.0251 0.01580.0171 1.9724 NT 56 25.9 0.0398 NT 0.0308 5.9704 NT 57 0.5 0.0355 NT0.0977 >10 NT 58 −2.0 0.0100 NT 0.0017 0.7129 NT 59 0.6 0.1259 NT0.1005 >10 NT 60 0.8 0.0219 NT 0.0149 2.3442 NT 61 11.2 0.0040 NT 0.002610.0000 NT 62 14.1 0.0063 NT 0.0196 >10 NT

What is claimed:
 1. A compound of formula I

or an enantiomer or diastereomer thereof; or a pharmaceuticallyacceptable salt thereof; wherein: n is an integer from 0-1; X is CH₂when n is 0, or X is CH₂ or oxygen when n is 1; R₁ is phenyl orpyridinyl, wherein the phenyl or pyridinyl is optionally substitutedwith halogen or alkyl; and R₂ is phenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl or thiophenyl, wherein thephenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,thiazolyl or thiophenyl is optionally substituted with halogen, alkyl,hydroxy or alkoxy.
 2. The compound of claim 1, wherein n is
 0. 3. Thecompound of claim 1, wherein n is
 1. 4. The compound of claim 1, whereinX is CH₂.
 5. The compound of claim 1, wherein X is oxygen.
 6. Thecompound of claim 1, wherein R₁ is phenyl optionally substituted withhalogen or alkyl.
 7. The compound of claim 1, wherein R₁ is phenylsubstituted with halogen or alkyl.
 8. The compound of claim 1, whereinR₁ is phenyl substituted with halogen and alkyl.
 9. The compound ofclaim 1, wherein R₁ is pyridinyl optionally substituted with halogen oralkyl.
 10. The compound of claim 1, wherein R₁ is pyridinyl substitutedwith halogen or alkyl.
 11. The compound of claim 1, wherein R₁ ispyridinyl substituted with halogen and alkyl.
 12. The compound of claim1, wherein R₂ is phenyl optionally substituted with halogen.
 13. Thecompound of claim 1, wherein R₂ is phenyl substituted with fluorine. 14.The compound of claim 1, wherein R₂ is pyridinyl optionally substitutedwith halogen, alkyl, hydroxy or alkoxy.
 15. The compound of claim 1,wherein R₂ is pyridinyl substituted with halogen, alkyl or alkoxy. 16.The compound of claim 1, wherein R₂ is pyridinyl substituted withfluorine or chlorine.
 17. The compound of claim 1, wherein R₂ ispyridinyl substituted with methyl or trifluoromethyl.
 18. The compoundof claim 1, wherein R₂ is pyridinyl substituted with methoxy,difluoromethoxy, trifluoromethoxy or ethoxy.
 19. The compound of claim1, wherein R₂ is pyrazinyl.
 20. The compound of claim 1, wherein R₂ ispyrimidinyl optionally substituted with halogen.
 21. The compound ofclaim 1, wherein R₂ is pyrimidinyl substituted with fluorine orchlorine.
 22. The compound of claim 1, wherein R₂ is pyrrolyl.
 23. Thecompound of claim 1, wherein R₂ is pyrazolyl optionally substituted withhalogen, alkyl, hydroxy or alkoxy.
 24. The compound of claim 1, whereinR₂ is pyrazolyl substituted with methyl.
 25. The compound of claim 1,wherein R₂ is thiazolyl optionally substituted with halogen, alkyl,hydroxy or alkoxy.
 26. The compound of claim 1, wherein R₂ is thiazolylsubstituted with methyl.
 27. The compound of claim 1, wherein R₂ isthiophenyl optionally substituted with halogen, alkyl, hydroxy oralkoxy.
 28. The compound of claim 1, wherein R₂ is thiophenylsubstituted with fluorine or chlorine.
 29. The compound of claim 1,wherein R₂ is thiophenyl substituted with methyl.
 30. A compoundselected from the group consisting of11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-[(2,4-Dichlorophenyl)carbonyl]-3-(5-fluoropyrimidin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-3-(5-Chloropyridin-2-yl)-11-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-thiophen-2-yl-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S*,10R*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6R*,10S*)-11-{[3-Chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-3-(5-methylthiophen-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyridin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-3-pyrazin-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-pyridin-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(5-fluoropyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(3-methyl-1H-pyrazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-4-fluoro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Methyl-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-3-(1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(2-methyl-1,3-thiazol-4-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-3-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-methyl-1,3-thiazol-5-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-3-(5-Chlorothiophen-2-yl)-10-{[3-chloro-2-(trifluoromethyl)pyridin-4-yl]carbonyl}-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-thiophen-2-yl-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(6S,9R)-10-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(1H-pyrrol-2-yl)-6,7,8,9-tetrahydro-5H-6,9-epimino[1,2,4]triazolo[4,3-a]azepine;(2-chloro-4-fluoro-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(3-chloro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;((2-methyl-3-(trifluoromethyl)phenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(3-methyl-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2,4-dichloro-3-fluorophenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)(3-(pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(3-fluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(3,5-difluoropyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;((2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-6-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(diffluoromethoxy)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-hydroxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-ethoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-isopropoxypyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-methylpyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)(3-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8,9,10-hexahydro-6,10-epimino[1,2,4]triazolo[4,3-a]azocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyrazin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(pyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyrimidin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-chloro-3-(trifluoromethyl)phenyl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichloro-4-fluorophenyl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone;((6R,10S)-3-(1H-pyrazol-3-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2,3-dichlorophenyl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(4-fluorophenyl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoro-4-methoxypyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-fluoro-3-(trifluoromethyl)phenyl)methanone;((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(4-(difluoromethoxy)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(5-fluoro-6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(4-(trifluoromethyl)pyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(6-methylpyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)(2-methyl-3-(trifluoromethyl)phenyl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(3-fluoropyridin-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-2-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-chloro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2,3-dichloro-4-fluorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-methyl-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(2-fluoro-3-(trifluoromethyl)phenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone;and(2,3-dichlorophenyl)((6R,10S)-3-(thiazol-4-yl)-6,7,9,10-tetrahydro-5H-6,10-epimino[1,2,4]triazolo[3,4-d][1,5]oxazocin-11-yl)methanone.31. A pharmaceutical composition comprising a compound according toclaim 30 and at least one pharmaceutically acceptable excipient.
 32. Amethod of treating a subject suffering from or diagnosed with a disease,disorder, or medical condition mediated by P2X7 receptor activity,comprising administering to the subject an effective amount of acompound according to claim
 1. 33. The method of claim 32, wherein thedisease, disorder, or medical condition mediated by P2X7 receptoractivity is selected from the list consisting of: rheumatoid arthritis,osteoarthritis, psoriasis, septic shock, allergic dermatitis, asthma,allergic asthma, mild to severe asthma, steroid resistant asthma,idiopathic pulmonary fibrosis, allergic rhinitis, chronic obstructivepulmonary disease; airway hyper-responsiveness, diseases of the nervousand neuro-immune system, acute and chronic pain states of neuropathicpain, inflammatory pain, spontaneous pain, diabetic neuropathy,postherpetic neuralgia, low back pain, chemotherapy-induced neuropathicpain, fibromyalgia, diseases involved with and without neuroinflammationof the central nervous system, mood disorders, major depression, majordepressive disorder, treatment resistant depression, bipolar disorder,anxious depression, anxiety, cognition, sleep disorders, multiplesclerosis, epileptic seizures, Parkinson's disease, schizophrenia,Alzheimer's disease, Huntington's disease, autism, spinal cord injuryand cerebral ischemia/traumatic brain injury, stress-related disorders,diseases of the cardiovascular, metabolic, gastrointestinal andurogenital systems such as diabetes, diabetes mellitus, thrombosis,irritable bowel syndrome, irritable bowel disease, Crohn's disease,ischemic heart disease, ischaemia, hypertension, cardiovascular disease,myocardial infarction, and lower urinary tract dysfunction such asincontinence, lower urinary tract syndrome, Polycystic Kidney Disease,Glomerulonephritis, skeletal disorders, osteoporosis, osteopetrosis, andglaucoma, interstitial cystitis, cough, ureteric obstruction, sepsis,Amyotrophic Lateral Sclerosis, Chaga's Disease, chlamydia,neuroblastoma, Tuberculosis, and migraine.
 34. The method of claim 32,wherein the disease, disorder, or medical condition is treatmentresistant depression.